Crystal structure, Hirshfeld, computational biomolecular investigations, and MTT assay studies of amino pyrimidine derivative as EGFR kinase domain inhibitor

2022 ◽  
pp. 132416
Author(s):  
RaviKumar Chandrasekaran ◽  
S. Murugavel ◽  
Mridula Guin ◽  
T. Silambarasan
Keyword(s):  
Crystal Structure ◽  
Mtt Assay ◽  
Kinase Domain ◽  
Pyrimidine Derivative ◽  
Amino Pyrimidine ◽  
Egfr Kinase

scholarly journals Structure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhenfang Du ◽  
Benjamin P. Brown ◽  
Soyeon Kim ◽  
Donna Ferguson ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Tandem Duplication ◽  
Function Analysis ◽  
Treatment Strategies ◽  
Kinase Domain ◽  
Time Resolved ◽  
Egfr Activation ◽  
Domain Duplication ◽  
Activation Mechanisms ◽  
Potential Therapeutic Intervention ◽  
Egfr Kinase

AbstractMechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.

scholarly journals Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis

Structure ◽  
1999 ◽  
Vol 7 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Michele A McTigue ◽  
John A Wickersham ◽  
Chris Pinko ◽  
Richard E Showalter ◽  
Camran V Parast ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Vascular Endothelial ◽  
Key Enzyme ◽  
Endothelial Growth Factor

scholarly journals PAS-mediated Dimerization of Soluble Guanylyl Cyclase Revealed by Signal Transduction Histidine Kinase Domain Crystal Structure

2007 ◽  
Vol 283 (2) ◽  
pp. 1167-1178 ◽  
Author(s):  
Xiaolei Ma ◽  
Nazish Sayed ◽  
Padmamalini Baskaran ◽  
Annie Beuve ◽  
Focco van den Akker
Keyword(s):  
Crystal Structure ◽  
Signal Transduction ◽  
Guanylyl Cyclase ◽  
Histidine Kinase ◽  
Soluble Guanylyl Cyclase ◽  
Kinase Domain

scholarly journals Comparable rate of EGFR kinase domain mutation in lung adenocarcinomas from Chinese male and female never-smokers

2010 ◽  
Vol 31 (5) ◽  
pp. 647-648 ◽  
Author(s):  
Yi-hua Sun ◽  
Rong Fang ◽  
Bin Gao ◽  
Xiang-kun Han ◽  
Jun-hua Zhang ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Comparable Rate ◽  
Male And Female ◽  
Kinase Domain Mutation ◽  
Never Smokers ◽  
Lung Adenocarcinomas ◽  
Chinese Male ◽  
Egfr Kinase

scholarly journals Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC

2018 ◽  
Vol 144 (11) ◽  
pp. 2677-2682 ◽  
Author(s):  
Jinguang Wang ◽  
Xingya Li ◽  
Xingyang Xue ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Targeted Therapies ◽  
Kinase Domain ◽  
Domain Duplication ◽  
Egfr Kinase

scholarly journals Molecular docking based screening of novel designed chalcone series of compounds for their anti-cancer activity targeting EGFR kinase domain

2015 ◽  
Vol 11 (7) ◽  
pp. 322-329 ◽  
Author(s):  
Chennu Rao ◽  
◽  
Rajendra Prasad Yejella ◽  
Rehman Rehman ◽  
Syed Hussain Basha ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Kinase Domain ◽  
Anti Cancer ◽  
Cancer Activity ◽  
Egfr Kinase

scholarly journals Crystal structure of the kinase domain of serum and glucocorticoid-regulated kinase 1 in complex with AMP-PNP

2007 ◽  
Vol 16 (12) ◽  
pp. 2761-2769 ◽  
Author(s):  
Baoguang Zhao ◽  
Ruth Lehr ◽  
Angela M. Smallwood ◽  
Thau F. Ho ◽  
Kathleen Maley ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Kinase Domain

scholarly journals Lung adenocarcinoma patient with an EGFR kinase domain duplication (KDD) and the response to icotinib

2018 ◽  
Vol 10 (5) ◽  
pp. E359-E363 ◽  
Author(s):  
You-Cai Zhu ◽  
Wen-Xian Wang ◽  
Chun-Wei Xu ◽  
Qing-He Tan ◽  
Jian-Ying Li ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Domain ◽  
Domain Duplication ◽  
Lung Adenocarcinoma Patient ◽  
Egfr Kinase

scholarly journals EGFR kinase domain mutation positive lung cancers are sensitive to intrapleural perfusion with hyperthermic chemotherapy (IPHC) complete treatment

Oncotarget ◽  
2015 ◽  
Vol 7 (3) ◽  
pp. 3367-3378 ◽  
Author(s):  
Hongjuan Zhang ◽  
Cheng Zhan ◽  
Ji Ke ◽  
Zhiqiang Xue ◽  
Aiqun Zhang ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Lung Cancers ◽  
Hyperthermic Chemotherapy ◽  
Complete Treatment ◽  
Kinase Domain Mutation ◽  
Egfr Kinase
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